Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases. (Cuypers et al., J. Biol. Chem. 257:7086 (1982)). Proteases are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, reproduction and the immune reaction to foreign cells and organisms. Aberrant proteolysis is associated with a number of disease states in man and other mammals. The human neutrophil proteases, elastase and cathepsin G, have been implicated as contributing to disease states marked by tissue destruction. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs, Sandler, ed., University Park Press, Baltimore, (1980)). Additional proteases such as plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, and kallikreins play key roles in the normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal.
Serine proteases include such enzymes as elastase (human leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, chymotrypsin, trypsin, thrombin, Factor Xa and kallikreins.
The serine protease thrombin occupies a central role in hemostasis and thrombosis, and as a multifactorial protein, induces a number of effects on platelets, endothelial cells, smooth muscle cells, leukocytes, the heart, and neurons. (Tapparelli et al., Trends in Pharmacological Sciences 14:366-376 (1993); Lefkovits and Topol, Circulation 90(3):1522-1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)). Activation of the coagulation cascade through either the intrinsic pathway (contact activation) or the extrinsic pathway (activation by exposure of plasma to a non-endothelial surface, damage to vessel walls or tissue factor release) leads to a series of biochemical events that converge on thrombin. Thrombin cleaves fibrinogen ultimately leading to a hemostatic plug (clot formation), potently activates platelets through a unique proteolytic cleavage of the cell surface thrombin receptor (Coughlin, Seminars in Hematology 31(4):270-277 (1994)), and autoamplifies its own production through a feedback mechanism. Thus, inhibitors of thrombin function have therapeutic potential in a host of cardiovascular and non-cardiovascular diseases, including: myocardial infarction; unstable angina; stroke; restenosis; deep vein thrombosis; disseminated intravascular coagulation caused by trauma, sepsis or tumor metastasis; hemodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypercoagulability during chemotherapy; Alzheimer's disease; Down's syndrome; fibrin formation in the eye; and wound healing. Other uses include the use of said thrombin inhibitors as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.
Factor Xa is another serine protease in the coagulation pathway. Factor Xa associates with Factor Va and calcium on a phospholipid membrane thereby forming a prothrombinase complex. This prothrombinase complex then converts prothrombin to thrombin. (Claeson, Blood Coagulation and Fibrinolysis 5:411-436 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)). Inhibitors of Factor Xa are thought to offer an advantage over agents that directly inhibit thrombin since direct thrombin inhibitors still permit significant new thrombin generation (Lefkovits and Topol, Circulation 90(3):1522-1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)) because one molecule of Factor Xa may be able to generate up to 138 molecules of thrombin (Elodi et al., Thromb. Res. 15 (617-619 (1979)).
Several specific inhibitors of Factor Xa have been reported. Both synthetic and protein inhibitors of Factor Xa have been identified, and these include, for example, antistasin (“ATS”) and tick anticoagulant peptide (“TAP”). ATS, which is isolated from the leech, Haementerin officinalis, contains 119 amino acids and has a Ki for Factor Xa of 0.05 nM. TAP, which is isolated from the tick, Ornithodoros moubata, contains 60 amino acids and has a Ki for Factor Xa of about 0.5 nM.
ATS and TAP have not been developed clinically. One major disadvantage of these two inhibitors is that administration of the required repeated doses causes the generation of neutralizing antibodies, thus limiting their potential clinical use. Moreover, the sizes of TAP and ATS render oral administration impossible, further restricting the number of patients able to benefit from these agents.
A specific inhibitor of Factor Xa would have substantial practical value in the practice of medicine. In particular, a Factor Xa inhibitor would be effective under circumstances where the present drugs of choice, heparin and related sulfated polysaccharides, are ineffective or only marginally effective. Thus, there exists a need for a low molecular weight, Factor Xa-specific blood clotting inhibitor that is effective, but does not cause unwanted side effects.
Low molecular weight, Factor Xa-specific blood clotting inhibitors, have been described in International Application WO 9529189. Indole derivatives as low molecular weight, Factor Xa-specific blood clotting inhibitors have been proposed in International Application 99338000.
WO 2004058743 discloses substituted nitrogen-containing heterobicycles and uses thereof as Faxtor Xa inhibitors.
WO 2004050636 discloses imidazole derivatives as Factor Xa inhibitors.
WO 2004056815 discloses pyrazole derivatives as Factor Xa inhibitors.
WO 2003044014 discloses indole-2 carboxamides as Faxtor Xa inhibitors.
WO 2002051831 discloses oxybenzamide derivatives as Factor Xa inhibitors.
WO 2002046159 discloses guanidine and amidine derivatives as Factor Xa inhibitors.
WO 2004002477 discloses 2-(phenyl)-2H-pyrazole-3-carboxylic-acid-N-4-(thioxo-heterocyclyl)-phenyl-amide derivatives and corresponding imino-heterocyclyl derivatives as Factor Xa inhibitors.
WO 2004002405 discloses amino-bicyclic pyrazinones and pyridinones as Factor Xa inhibitors.
However, it is desirable that such inhibitors have advantageous pharmacological properties, for instance high stability in plasma and liver and high selectively versus other serine proteases. A need continues to exist for non-peptidic compounds that are potent and selective protease inhibitors, and which possess greater bioavailability and fewer side effects than currently available protease inhibitors. Accordingly, new classes of potent protease inhibitors, characterized by potent inhibitory capacity and low mammalian toxicity, are potentially valuable therapeutic agents for a variety of conditions, including treatment of a number of mammalian proteolytic disease states. In particular there continues to be a need for compounds that selectively inhibit Factor Xa.